Functional and Structural Study of Alphavirus Receptors

Abstract

Alphaviruses are single-stranded, positive sense RNA viruses that can cause epidemic polyarthritis or encephalitis in humans and animals. Encephalitic alphaviruses include eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), and Venezuelan equine encephalitis virus (VEEV). While EEEV and VEEV currently cause regionally contained outbreaks, their emergence into epidemics could be devastating. WEEV historically caused explosive epidemics of viral encephalitis in North America, but has since rapidly declined with the last case documented in the 1990s, a poorly understood process termed “submergence”. Alphaviruses enter host cells through attachment to specific protein receptors on the cell surface, a critical step targeted by antibodies and entry-blocking therapeutics. Here, we combine functional assays with in vitro, in vivo models and cryogenic electron microscopy (cryo-EM) to characterize the interaction of EEEV with its previously identified receptor, and of WEEV with newly identified receptors in this study. Our results provide insight into the ability of EEEV and WEEV to invade the central nervous system, and the molecular basis for the submergence of WEEV as a human and veterinary pathogen in North America, with implications for outbreak preparedness and the development of antiviral therapeutics.